The concept of vaccination (the inoculation of individuals with pathogen-derived material to induce immunity) has been known since the late 18th century.
Vaccine approaches using either live attenuated or inactive pathogens are undersirable for many reasons, including the risk of reversion to wild-type. For this reason there has been interest in using a “sub-unit” vaccine approach whereby only the key antigenic sequences of the pathogen are included in a vehicle or carrier.
In order to develop a sub-unit vaccine, it is necessary to identify the key antigen(s) in a pathogen. Complex pathogens encode for large numbers of potential antigens (100's-1000's) and this complexity precludes serial testing approaches to identify those antigens that induce protective and/or effective responses.
To date, the master criterion for assessing whether an candidate antigen has potential for use in a vaccine has been its capacity for inducing an immune response. In other words, attention is focussed on those antigens which potentiate the strongest immune response.
However, the induction of a response is not the same as the induction of protection. The immune system is reactive and during an infectious challenge will respond to a large number of antigens. Unfortunately most of the induced responses (especially where the pathogen is antigenically complex) are not effective in controlling the pathogen.
Vaccine candidates which are capable of inducing robust pathogen-specific immune responses and not necessarily protective against disease, e.g. may not protect against subsequent pathogenic challenge (Melby et al (2001) 69:4719-4725; Héchard et al (2004) 53:861-868; Stober et al (2006) as above).
Studies with DNA pool vaccines for antigenically complex pathogens have shown that only a small number of vaccine candidates are protective, and some actually exacerbate disease (Stober et al (2006) Vaccine 24: 2602-2616; Stemke-Hale et al (2005) Vaccine 23:3016-3025; Melby et al (2000) Infection and Immunity 68:5595-5602). When serial fractionation was used to screen vaccine candidates for the fungal pathogen Coccidioides immitis, a single protective gene was identified from a cDNA library containing 800-1000 genes (Ivey et al (2003) 4359-4367).
Interestingly, it has been shown that, for antigenically complex pathogens (such as parasites) protective antigens localise to a small number of loci within the genome (Blake et al (2004) Mol & Biochem Parasitol 138:143-52; Martinelli et al (2005) PNAS 102:814-819).
When using immune-response generation as a selection criterion for vaccine candidates, the “response” assays can be refined to assay for so-called “correct” types of response (i.e. the type(s) of immune response which are associated with protection), for example using IFNγ production as an indicator of Th1 T cell response. Although these types of, strategy serve to reduce the numbers of antigens that are identified, the basis of T cell responses is such that most of these T cells that produce the “right kind of response” are not effective in vivo.
Moreover, in many cases effective or protective responses are directed to a small subset of the “responded to” antigens but more than one specificity of response is required for protection.
There is thus a need to identify the effective/protective response within the large repertoire of responding cells generated during an immune response to a pathogen.
There is also a need to identify the antigen(s) responsible for generation of the protective/effective immune response.